Study Objective

To evaluate whether the treatment effect of high-dose melatonin therapy in patients with ST-segment elevation myocardial infarction (STEMI) is influenced by the time to administration relative to the cardiac event.

Design

The authors performed a post hoc analysis of the Melatonin Adjunct in the Acute Myocardial Infarction Treated With Angioplasty (MARIA) trial (NCT00640094), which randomized STEMI patients to melatonin (intravenous and intracoronary bolus) or placebo during primary percutaneous coronary intervention (PCI).

Participants

The MARIA trial included 146 patients presenting with STEMI within 6 hours of chest pain onset. Participants were randomized to receive intravenous and intracoronary melatonin (n=73) or placebo (n=73) during primary PCI.

Study Medication and Dosage

Participants in the MARIA trial received 12 mg of melatonin intravenously as a continuous infusion for 60 minutes. This dose raises melatonin blood levels approximately 12,000 times higher than the highest nocturnal levels. In addition, patients received a bolus of 2 mg of intracoronary melatonin given through the PCI-guiding catheter after restoring the blood flow to the infarct-related artery.

Outcome Measures

The primary efficacy endpoint of the original MARIA trial was to determine whether melatonin treatment reduces infarct size determined by the cumulative release of alpha-hydroxybutyrate dehydrogenase (area under the curve: 0 to 72 h). Secondary end points were clinical events occurring within the first 90 days: death, sustained ventricular arrhythmias, resuscitation from cardiac arrest, cardiogenic shock, heart failure, major bleedings, stroke, need for revascularization, recurrent ischemia, re-infarctions and rehospitalization.1

There have been strong hints over the past year to suggest that melatonin should have been useful.

The study reviewed here is a secondary, post-hoc analysis of data from the MARIA trial. The authors divided the patients treated in the MARIA study into 3 groups (tertiles) based on the time between symptom onset to “balloon time” (when balloon is inflated to restore flow during PCI):

First tertile: 136 ± 23 minutes

Second tertile:196 ± 19 minutes

Third tertile: 249 ± 41 minutes

They used statistical analyses to assess the relationships between treatment effect and time.

Key Findings

This is the second of 2 important publications from the MARIA study on melatonin and heart attacks this year. This study evaluated whether the treatment effect of melatonin therapy in patients with STEMI is influenced by the time to administration.

The original MARIA trial began in 2007 and was a single-center, prospective, randomized, double-blind, placebo-controlled, phase 2 study of the intravenous administration of melatonin. Results of this trial were reported in January 2017.2

The present analysis was published in August 2017 and examined the effect of time to melatonin administration in MIs. The information from both these studies is relevant.

The initial January publication of the MARIA results showed little benefit of melatonin administration. Baseline characteristics between groups were similar. Myocardial infarct size as determined by MRI within a week of procedure did not differ between melatonin and placebo groups (P=0.63). Infarct size at 130 days post-primary PCI, performed in 91 patients (72.8%), did not show statistically significant differences between groups (P=0.27). Recovery of left ventricular volumes and ejection fraction (LVEF) from 6 to 130 days post-procedure was not significantly different though the placebo group trended toward higher volumes (60.0 ± 10.4% vs 53.1 ± 12.5%; P=0.008). Both left ventricular end-diastolic and end-systolic volumes were lower in the placebo group (P=0.01). The incidence of adverse events at 1 year was comparable in both groups (P=0.150). Thus, in a nonrestricted STEMI population, intravenous and intracoronary melatonin was not associated with a reduction in infarct size and has an unfavorable effect on the ventricular volumes and LVEF evolution.2

In those patients in the first tertile, who underwent the procedure earlier after symptom onset, infarct size was significantly smaller in the melatonin-treated subjects compared with placebo (14.6 ± 14.2 vs 24.9 ± 9.0%; P=0.003).

On the other hand, treatment with melatonin was associated with larger infarct size in the patients included in the third tertile (20.5 ± 8.7% vs 11.2 ± 5.2%; P=0.001).

Practice Implications

Everyone would love to have a simple intervention that can be given to a patient during and after an MI that would lessen the long-term damage and speed recovery.

In these reviews we generally report good news; the MARIA study is something of an exception to that rule. The intervention failed to provide benefit to these patients, yet honestly it isn’t an intervention a naturopathic physician would consider—it is beyond our scope and certainly outside of our philosophy.

There have been strong hints over the past year to suggest that melatonin should have been useful. A June 2017 paper reported that melatonin ameliorates myocardial ischemia/reperfusion injuries in rats.3 It also suppresses platelet activation triggered by cardiac ischemia/reperfusion injury.4

Perhaps the MARIA melatonin dose was just too large or too intense. Perhaps it reached the heart too late to be of help.

A year ago Javanamard et al reported that they had conducted a double-blind, randomized controlled trial of 39 patients (32 men and 7 women) with 3-vessel coronary disease who underwent coronary bypass grafting surgery. Of these patients, 20 received 10 mg oral melatonin before bed for 1 month. The 19-person control group received placebo. Mean levels of 3 markers of endothelial cell function including intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and C-reactive protein (CRP) showed statistically significant reductions in the melatonin group. There was a statistically significant decrease in serum nitric oxide (NO) in the control group but no change in the melatonin group.5

This is confusing. We had hoped that the MARIA study would provide clear justification to aggressively enlist melatonin for use in patients who are having heart attacks or who have undergone balloon procedures as a way to limit tissue damage and speed recovery. In this instance timing makes a big difference; early administration might still prove useful but later treatment might backfire.

Harvard researcher Eva Schernhammer reported in May 2017 that there was a significant inverse association between melatonin secretion and risk of MI, with lower melatonin secretion significantly associated with a higher risk of MI. The odds ratio (OR) for every one unit lower log-transformed sulfatoxymelatonin/creatinine ratio was 1.51 (95% confidence interval [CI]: 1.16-1.96). Women in the highest category had an estimated absolute risk of MI of 84 cases per 100,000 person-years compared with 197 cases per 100,000 person-years in the lowest category. The association was strongly modified by BMI (P-value for interaction=0.02).6

Clearly there is potential for melatonin to be of help, we probably just need the right dose at the right time. We’re not there yet.

About the Author

Jacob Schor ND, FABNO, is a graduate of National College of Naturopathic Medicine, Portland, Oregon, and now practices in Denver, Colorado. He served as president to the Colorado Association of Naturopathic Physicians and is on the board of directors of the Oncology Association of Naturopathic Physicians. He is recognized as a fellow by the American Board of Naturopathic Oncology. He serves on the editorial board for the International Journal of Naturopathic Medicine, Naturopathic Doctor News and Review (NDNR),and Integrative Medicine: A Clinician's Journal. In 2008, he was awarded the Vis Award by the American Association of Naturopathic Physicians. His writing appears regularly in NDNR, the Townsend Letter, and Natural Medicine Journal, where he is the Abstracts & Commentary editor.